Though proteins produced by gene recombinant technology should have an amino acid sequence predicted from the gene sequence, a number of variants may actually be produced. This is due to known or novel in vivo (post-transcription) modification or naturally occurring (non-enzymatic) proteolysis (R. J. Harris, J. Chromatogr. A 705 (1995) 129-134). Since proteins for use as ingredients of pharmaceutical drugs are produced by gene recombinant technology utilizing in vivo biosynthetic processes, there is a possibility that subtypes having different molecular structures may be produced. The kinds and contents of subtypes define the quality of pharmaceutical drugs, and therefore it is important to characterize the subtype profiles and assure their usefulness as pharmaceutical compositions.
IL-6 is a cytokine which is also called B cell stimulating factor 2 (BSF2) or interferon β2. IL-6 was discovered as a differentiation factor involved in the activation of B-lymphatic cells (Hirano, T. et al., Nature (1986) 324, 73-76). Thereafter, it was found to be a multifunctional cytokine that influences various functions of the cell (Akira, S. et al., Adv. in Immunology (1993) 54, 1-78). IL-6 has been reported to induce the maturation of T-lymphatic cells (Lotz, M. et al., J. Exp. Med. (1988) 167, 1253-1258).
IL-6 transmits its biological activity through two types of proteins on the cell. One type is interleukin-6 receptor (IL-6R), a ligand-biding protein with a molecular weight of about 80 kD, to which IL-6 binds (Taga, T. et al., J. Exp. Med. (1987) 166, 967-981; Yamasaki, K. et al., Science (1987) 241, 825-828). IL-6R occurs not only in the membrane-bound form that penetrates through and is expressed on the cell membrane but also as a soluble IL-6R consisting mainly of the extracellular region.
Anti-IL-6R antibody has been described in several reports (Novick D. et al., Hybridoma (1991) 10, 137-146, Huang; Y. W. et al., Hybridoma (1993) 12, 621-630; International Patent Publication WO 95-09873; French Patent Application FR 2694767; U.S. Pat. No. 521,628). A known Humanized PM-1 antibody was obtained by transplanting the complementarity determining region (CDR) of a mouse antibody PM-1 (Hirata, Y. et al., J. Immunol. (1989) 143, 2900-2906), to a human antibody (International Patent Publication WO 92-19759).
However, subtypes of the humanized PM-1 antibody are not known.    Patent document 1: WO 92/19759    Patent document 2: Japanese Unexamined Patent Publication (Kokai) No. 8-99902    Patent document 3: French Patent Publication FR 2694767    Patent document 4: U.S. Pat. No. 521,628    Non-patent document 1: R. J. Harris, J. Chromatogr. A 705 (1995) 129-134    Non-patent document 2: Hirano, T. et al., Nature (1986) 324, 73-76    Non-patent document 3: Akira, S. et al., Adv. in Immunology (1993) 54, 1-78    Non-patent document 4: Lotz, M. et al., J. Exp. Med. (1988) 167, 1253-1258    Non-patent document 5: Taga, J. Exp. Med. (1987) 166, 967-981    Non-patent document 6: Yamasaki, K. et al., Science (1987) 241, 825-828    Non-patent document 7: Novick, D. et al., Hybridoma (1991) 10, 137-146    Non-patent document 8: Huang, Y. W. et al., Hybridoma (1993) 12, 621-630    Non-patent document 9: Hirata, Y. et al., J. Immunol. (1989) 143, 2900-2906